Triazole compounds with dopamine-D3-receptor affinity

ABSTRACT

Triazole compounds of the following formula                    
     where R 1 , R 2 , A and B have the meanings given in the description are described. The compounds according to the invention possess a high affinity for the dopamine D 3  receptor and can therefore be used for treating diseases which respond to the influence of dopamine D 3  ligands.

The invention relates to triazole compounds and to the use of these compounds. These compounds possess valuable therapeutic properties and can be used for treating diseases which respond to the influence of dopamine D₃ receptor ligands.

Compounds of the type which is under discussion here and which possess physiological activity are already known. Thus, WO 94/25013; 96/02520; 97/43262; 97/47602; 98/06699; 98/49145; 98/50363; 98/50364 and 98/51671 describe compounds which act on the dopamine receptors. DE 44 25 144 A, WO 96/30333, WO 97/25324, WO 97/40015, WO 97/47602, WO 97/17326, EP 887 350, EP 779 284 A and Bioorg. & Med. Chem. Letters 9 (1999) 2059-2064 disclose further compounds which possess activity as dopamine D₃ receptor ligands. U.S. Pat. Nos. 4,338,453; 4,408,049 and 4,577,020 disclose triazole compounds which possess antiallergic or antipsychotic activity. WO 93/08799 and WO 94/25013 describe compounds of the type which is under discussion here and which constitute endothelin receptor antagonists. Additional triazole compounds, which inhibit blood platelet aggregation and which have a hypotensive effect are described in Pharmazie 46 (1991), 109-112. Further triazole compounds which possess physiological activity are disclosed in EP 691 342, EP 556 119, WO 97/10210, WO 98/24791, WO 96/31512 and WO 92/20655.

Neurons obtain their information by way of G protein-coupled receptors, inter alia. There are a large number of substances which exert their effect by way of these receptors. One of them is dopamine.

A number of facts about the presence of dopamine, and its physiological function as a neuron transmitter, are known with certainty. Disturbances of the dopaminergic transmitter system result in diseases such as schizophrenia, depression and Parkinson's disease. These, and other, diseases are treated with drugs which interact with the dopamine receptors.

By 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the D₁ and D₂ receptors.

More recently, a third subtype has been found, namely the D₃ receptor, which appears to mediate some of the effects of the antipsychotic and anti-Parkinson agents (J. C. Schwartz et al., The Dopamine D₃ Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514).

Since D₃ receptors are chiefly expressed in the limbic system, it is assumed that while a selective D₃ ligand would probably have the properties of known antipsychotic agents, it would not have their dopamine D₃ receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D₃ Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347, 146 (1990)).

Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D₃ receptor and a low affinity for the D₂ receptor. These compounds are consequently selective D₃ ligands.

The present invention relates, therefore, to the compounds of the formula I:

where

R¹ is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₃-C₆-cycloalkyl or phenyl;

R² is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR³, CONR³R⁴, NR³R⁴, SO₂R³, SO₂NR³R⁴, or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered-heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COR³, NR³R⁴, NO₂, SO₂R³, SO₂NR³R⁴ and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C₁-C₆-alkyl, C₁-C₆-alkoxy, NR³R⁴, CN, CF₃, CHF₂ or halogen;

R³ and R⁴ are, independently of each other, H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, or phenyl;

A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, CONR³, COO, CO, C₃-C₆-cycloalkyl and a double or triple bond;

B is a radical of the following formula:

X is CH₂ or CH₂CH₂;

R⁵ is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₃-C₆-cycloalkyl, C₂-C₆-alkenyl, which may be substituted by halogen (1 or 2 halogen atoms), or C₂-C₆-alkynyl;

R⁶, R⁷ and R⁸ are, independently of each other, selected from H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, C₁-C₆-alkylthio, halogen or phenyl, OH, C₁-C₆-alkoxy, SH, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, NO₂, SO₂R³, SO₂NR³R⁴, CONR³R⁴, NHSO₂R³ and NR³R⁴;

and the salts thereof with physiologically tolerated acids.

The compounds according to the invention are selective dopamine D₃ receptor ligands which act in the limbic system in a regioselective manner and which, as a result of their low affinity for the D₂ receptor, have fewer side-effects than do the classic neuroleptic agents, which are D₂ receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D₃ ligands, i.e. they are effective for treating those diseases in which affecting (modulating) the dopamine D₃ receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of such diseases are diseases of the cardiovascular system and the kidneys, diseases of the central nervous system, in particular schizophrenia, affective disorders, neurotic stress and somatoform disorders, psychoses, parkinsonism, attention deficit disorders, hyperactivity in children, epilepsy, amnesic and cognitive disorders such as learning and memory impairment (impaired cognitive function), anxiety states, dementia, delirium, personality disorders, sleep disturbances (for example restless legs syndrome), disorders of the sex life (male impotence), eating disorders and addictive disorders. Moreover, they are useful in the treatment of stroke.

Addictive disorders include the pysychological disorders and behavioral disturbances caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impluse control disorders not elsewhere classified). Addictive substances are, for exampel: opioids (for example morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chloride canal complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylendioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimulants including caffeine. Addictive substances of particular concern are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.

The compounds according to the invention are preferably used for treating affective disorders; neurotic, stress and somatoform disorders and psychoses, e.g. schizophrenia.

Within the context of the present invention, the following expressions have the meanings given in conjunction with them:

Alkyl (also in radicals such as alkoxy, alkylthio, alkylamino etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular from 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC₁-C₆-alkyl, halogen or phenyl. In the case of a halogen substituent, the alkyl group can, in particular, encompass, 1, 2, 3 or 4 halogen atoms which can be located on one or more C atoms, preferably in the α or ω position. CF₃, CHF₂, CF₂Cl or CH₂F are particularly preferred.

Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.

Cycloalkyl is, in particular, C₃-C₆-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkylene radicals are straight-chain or branched. If A does not have a group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least four carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms.

If the alkylene groups comprise at least one of the Z groups, this or these groups can then be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of the A group (seen from the triazole radical). The radicals CONR² and COO are preferably arranged such that the carbonyl group is in each case facing the triazole ring. Particular preference is given to the compounds of the formula I in which A is —Z—C₃-C₆-alkylene, in particular —Z—CH₂CH₂CH₂—, —Z—CH₂CH₂CH₂CH₂—, —Z—CH₂CH═CHCH₂—, —Z—CH₂C(CH₃)═CHCH₂—,

—Z—CH₂CH(CH₃)CH₂— or a linear —Z—C₇-C₁₀-alkylene radical, with Z being bonded to the triazole ring. Z is preferably CH₂, O and, in particular, S. Preference is additionally given to A being —(CH₂)₄—, —(CH₂)₅—, —CH₂CH₂CH═CHCH₂—,

—CH₂CH₂C(CH₃)═CHCH₂— or —CH₂CH₂CH(CH₃)CH₂—.

Halogen is F, Cl, Br or I, preferably F or Cl.

R¹ is preferably H, C₁-C₆-alkyl or C₃-C₆-cycloalkyl.

If R² is an aromatic radical, this radical is then preferably one of the following radicals:

where

R⁹ to R¹¹ are H or the abovementioned substituents of the aromatic radical,

R¹² is H, C₁-C₆-alkyl or phenyl, and

T is N or CH.

If the phenyl radical is substituted, the substituents are preferably in the m position or the p position.

The aromatic radical is particularly preferably a group of the formula:

where R⁹, R¹⁰ and R¹² have the abovementioned meanings. The indicated phenyl, pyridyl, thiazolyl and pyrrole radicals are particularly preferred.

The radicals R⁹ to R¹¹ are preferably H, C₁-C₆-alkyl, OR³, CN, phenyl, which may be substituted by C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, CF₃ and halogen, and are, in particular, H, C₁-C₆-alkyl, OR³ and halogen. In this context, R³ has the abovementioned meanings.

Particularly preferably, R² is H, C₁-C₆-alkyl, NR³R⁴ (R³ and R⁴ are, independently of each other, H or C₁-C₆-alkyl), phenyl or a 5-membered aromatic heterocyclic radical which has 1 or 2 heteroatoms which are independently selected from N, S and O. The heterocyclic radical is preferably a pyrrole radical or a pyridine radical.

In the radical B, X is preferably CH₂CH₂.

Preferably, at least one of the radicals R⁶, R⁷ and R⁸ is H.

The radicals R⁶, R⁷ and R⁸ are preferably, and independently of each other, selected from H, C₁-C₆-alkyl, halogen-substituted C₁-C₆-alkyl, OH, C₁-C₆-alkoxy, C₁-C₆-alkylthio-C₁-C₆-alkyl, halogen, NO₂, CN, SO₂R³, SO₂NR³R⁴ and CONR³R⁴. Particularly preferably, the fused phenyl group has one or two substituents, i.e. one or two of the radicals R⁶, R⁷ and R⁸ is/are C₁-C₆-alkyl, halogen, CN, SO₂NR³R⁴, NO₂ or CF₃.

Particular preference is given to the compounds of formula I where

R¹ is H, C₁-C₆-alkyl or phenyl,

R² is H, C₁-C₆-alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl,

A is —SC₃-C₁₀-alkylene which can comprise a double bond or C₃-C₆-cycloalkyl, and

R⁶, R⁷ and R⁸ are selected from H, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, SO₂NR³R⁴, CN, NO₂ or CF₃.

The invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung [Advances in pharmaceutical research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basle and Stuttgart, 1966.

The compounds of the formula I can exhibit one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The respective tautomeric forms are also included in the invention.

The process for preparing the compounds of the formula I consist in

a) reacting a compound of the formula (II)

where Y¹ is a customary leaving group, such as Hal, alkylsulfonyloxy, arylsulfonyloxy, etc., with a compound of the formula (III)

HB  (III);

or

b) reacting a compound of the formula (IV)

where Z¹ is O or S, and A₁ is C₁-C₁₀-alkylene or a bond, with a compound of the formula (V)

Y¹—A²—B  (V)

where Y¹ has the abovementioned meaning and A² is C₂-C₁₀-alkylene, with A¹ and A² together having from 3 to 10 C atoms and A¹ and/or A² where appropriate comprising at least one group Z; or

c) reacting a compound of the formula (VI)

where Y¹ and A¹ have the abovementioned meanings, with a compound of the formula (VII)

H—Z¹—A—B  (VII)

where Z¹ has the abovementioned meanings; or

d) reversing the polarity of a compound of the formula (VIII)

using reagents which are known from the literature, such as 1,3-propanedithiol, KCN/water, TMSCN (trimethylsilyl cyanide) or KCN/morpholine, as described, for example, in

Albright Tetrahedron, 1983, 39, 3207 or

D. Seebach Synthesis 1969, 17 und 1979, 19 or

H. Stetter Angew. Chem. Int. Ed. 1976, 15, 639 or

van Niel et al. Tetrahedron 1989, 45, 7643

Martin et al. Synthesis 1979, 633,

to give the products (VIIIa) (using 1,3-propanedithiol by way of example)

and then chain-elongating with compounds of the formula (IX)

Y¹—A³—B  (IX)

where Y¹ has the abovementioned meaning and A³ is C₃-C₉-alkylene which can contain a group Z, with compounds of the formula (Ia)

where Z² is CO or a methylene group, and Z² and A² have together from 4 to 10 C atoms, being obtained after deprotecting or reducing, or

e) reacting a compound of the formula (VIII) with a compound of the formula (X)

Y²—A—B  (X)

where Y² is a phosphorane or a phosphonic ester, in analogy with customary methods, as described, for example, in Houben Weyl “Handbuch der Organischen Chemie” [Textbook of Organic Chemistry], 4th Edition, Thieme Verlag Stuttgart, Volume V/1b p. 383 ff, or Vol. V/1c p. 575 ff, or

f) reacting a compound of the formula (XI)

where Q is H or OH, with a compound of the formula III under reductive conditions in analogy with methods known from the literature, for example as described in J. Org. Chem. 1986, 50, 1927; or WO 92/20655, or

g) in order to prepare a compound of the formula (Ib)

where B¹ is a radical of the formula (XII)

reacting compounds of the formula (XIII) or (XIV),

with a compound of the formula (XV)

under reductive conditions.

The process for preparing a compound of the formula I where A comprises the groups COO or CONR³ consists in reacting a compound of the formula (XVI)

where Y³ is OH, OC₁-C₄-alkyl, Cl or, together with CO, an activated carboxyl group, and A⁴ is C₀-C₉-alkylene, with a compound of the formula (XVII)

B—A—Z³  (XVII)

where Z³ is OH or NHR³.

Compounds of the type (XV) can be synthesized by alkylating compounds of the formula (IV) with compounds of the formula (XVIII),

to give compounds of the formula (XIX),

subsequently carrying out hydrazinolysis to give compounds of the type (XX)

and then introducing the radical R⁵, by, for example, effecting a reductive amination (as described, for example, in J. Org. Chem. 1986, 50, 1927) using the corresponding aldehyde or by means of alkylation in the presence of a base.

Compounds of the formula XX can also be obtained by reacting compounds of the formula II with azides, such as sodium azide, and then reducing, as described, for example, in

H. Staudinger, Helv. Chim. Acta 1919, 2, 635 or

R. Carrie, Bull. Chem. Soc. Fr. 1985, 815.

Compounds of the formula XIII and XIV are known from the literature or can be prepared using known methods, as described, for example, in

A. van Vliet et al. J. Med. Chem. 1996, 39, 4233

M. Langlois Bioorg. Med. Chem. Lett. 1993, 3, 203

U. Hacksell J. Med. Chem. 1993, 36, 4221 or in WO 93/08799 or WO 95/04713.

The compounds of the formula (IV) type are either known or can be prepared using known methods, as described, for example, in A. R. Katritzky, C. W. Rees (ed.) “Comprehensive Heterocyclic Chemistry”, Pergamon Press, or “The Chemistry of Heterocyclic Compounds” J. Wiley & Sons Inc. NY and the literature which is cited therein, or in S. Kubota et al. Chem. Pharm. Bull. 1975, 23, 955 or Vosilevskii et al. Izv. Akad. Nauk. SSSR Ser. Khim. 1975, 23, 955.

In the above formulae, R¹, R², R⁵, R⁶, R⁷, R⁸, A, B and X have the meanings given in connection with formula I.

The compounds according to the invention, and the starting materials and the intermediates, can also be prepared in analogy with the methods which are described in the patent publications which were mentioned at the outset.

The above-described reactions are generally effected in a solvent at temperatures of between room temperature and the boiling temperature of the solvent employed. Examples of solvents which can be used are esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.

If desired, the reactions can be carried out in the presence of an acid-binding agent. Suitable acid-binding agents are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, sodium methoxide, sodium ethoxide, sodium hydride, or organometallic compounds, such as butyl lithium or alkyl magnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can also simultaneously serve as the solvent.

Processes (f) and (g) are effected under reducing conditions, e.g. using sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride, where appropriate in an acid medium or in the presence of a Lewis acid, such as zinc chloride, or by way of catalytic hydrogenation.

The crude product is isolated in a customary manner, for example by means of filtering, distilling off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by recrystallization from a solvent, by chromatography or by converting into an acid addition compound.

The acid addition salts are prepared in a customary manner by mixing the free base with the corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.

For treating the abovementioned diseases, the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly or intraperitoneally) in a customary manner. The administration can also be effected through the nasopharyngeal space using vapors or sprays.

The dosage depends on the age, condition and weight of the patient and on the type of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per patient and day when administered orally and from about 1 to above 500 mg per patient and day when administered parenterally.

The invention also relates to pharmaceuticals which comprise the compounds according to the invention. In the customary pharmacological administration forms, these pharmaceuticals are present in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. In this context, the active compounds can be worked up together with the customary pharmacological auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flow-regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and/or propellent gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight.

The following examples serve to explain the invention without limiting it.

EXAMPLES Example 1 3-[3-(N-(Indan-2-yl)propylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole Fumarate

1A Preparation of the Starting Compounds

1A1 2-N-Propylaminoindan 18.8 g (300 mmol) of sodium cyanoborohydride were added to a mixture of 20 g (150 mmol) of 2-aminoindan, 40.9 g (300 mmol) of zinc dichloride and 10.4 g (180 mmol) of propionaldehyde in 550 ml of methanol, and the whole was heated to boiling for 3.5 hours. For the working up, 460 ml of 1M sodium hydroxide solution was added to the mixture and this new mixture was extracted several times with ethyl acetate. The combined organic phases were washed with a saturated solution of sodium chloride and dried, and the solvent was removed under reduced pressure. Chromatographic purification of the crude product (silica gel, methylene chloride/methanol=9/1) yielded 7.8 g of a pale brown 45 oil.

Yield: 7.8 g (30% of theory); ¹H-NMR (DMSO-D₆): 0.9 (t, 3H); 1.4 (m, 2H); 2.5-2.7 (m, 4H); 3.0-3.1 (m, 2H); 3.3 (sbr, NH); 3.5 (m, 1H).

1A2 2-(N-(3-Chloropropyl)propylamino)indan

7.6 g (44 mmol) of 2-N-propylaminoindan were heated to boiling in 100 ml of acetonitrile, for 4 hours under reflux, together with 17.1 g (109 mmol) of 1-bromo-3-chloropropane, 9.0 g (138 mmol) of potassium carbonate and 3.3 g (150 mmol) of sodium iodide. The mixture was then filtered with suction through Celite, after which the solvent was evaporated under reduced pressure; the crude product was then used for the subsequent reaction.

1B Preparation of the End Product

6.1 g (26 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole (prepared by the method of Kubota et al., Chem. Pharm. Bull 1975, 23, 955) and 9.6 g (38 mmol) of the crude product obtained in 1A2 were heated, together with 2.8 g (19 mmol) of lithium hydroxide, at 80° C. for 2.5 hours, and with stirring, in 100 ml of DMF (dimethylformamide). The solvent was subsequently distilled off under reduced pressure and 500 ml of a saturated solution of sodium hydrogen carbonate were added to the residue; this mixture was then extracted several times with methyl tert-butyl ether and ethyl acetate. After drying and evaporating, 9.5 g of an oil remained, with this oil being purified by column chromatography (methylene chloride containing 0-3% methanol).

C₂₄H₃₀ON₄S (406) MS (m/z): 407 [M+H]⁺; 0.71 g of substance was isolated as the fumarate after precipitating in isopropanol/methyl tert-butyl ether. ¹H-NMR (CDCl₃): 0.9 (t, 3H); 1.5 (m, 2H); 1.9 (q, 2H); 2.6-3.2 (m, 10H); 3.5 (s, 3H); 3.6 (m, 1H); 6.6 (s, 2H); 7.2 (m, 4H); 7.5(m, 3H); 7.7. (m, 2H).

Example 2 3-[3-(N-(6-Methoxyindan-1-yl)propylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

6-Methoxy-1-propylaminoindan was obtained by the reductive amination of 6-methoxyindan-1-one with n-propylamine in the presence of zinc dichloride and sodium cyanoborohydride in methanol, as described in 1A1. After conversion into the chloropropyl compound, as described in 1A2, this latter was reacted with 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole, in analogy with 1B, with the compound of Example 2 being obtained.

C₂₅H₃₂N₄OS (436) MS (m/z): 436 [M+H]⁺; ¹H-NMR (CDCl₃): 0.8 (t, 3H); 1.5 (m, 2H); 1.9 (m, 3H); 2.0 (m, 1H); 2.45-2.9 (m, 6H); 3.2 (m, 1H), 3.3 (m, 1H); 3.6 (s, 3H); 3.7 (s, 3H); 4.6 (t, 1H); 6.8 (dd, 1H); 6.9 (d, 1H); 7.1 (d, 1H); 7.6 (m, 3H); 7.75 (m, 2H).

Example 3 3-[3-(6-Methylmercaptomethyl-1,2,3,4-tetrahydronaphth-2-ylamino)-propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

3A Preparation of the Starting Compound

3-(3-Aminopropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole 3-Mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole (11.8 g, 50 mmol) was heated, together with 13.8 g (50 mmol) of N-(3-bromopropyl)phthalimide and 1.2 g (50 mmol) of lithium hydroxide, at 100° C. for 3.5 hours, in 150 ml of DMF. After the mixture had cooled down, 1 l of water was added and this new mixture was extracted several times with methylene chloride; the organic phase was then dried and evaporated. 14.5 g (75% of theory) of 3-[4-methyl-5-phenyl-3-phthalimidopropylmercapto]-1,2,4(4H)-triazole were obtained. 14.5 g (38 mmol) of the above-described compound were reacted with 2.3 ml (46 mmol) of hydrazine hydrate in ethanol, and 9.7 g (39 mmol) of 3-(3-aminopropylmercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole were isolated.

Yield: 9.7 (quantitative); ¹H-NMR (CDCl₃): 1.6 (sbr, 2H); 2.0 (q, 2H); 2.9 (t, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 7.5 (m, 3H); 7.7 (m, 2H).

3B Preparation of the End Product

1.0 g (4 mmol) of the compound described in 3A was initially introduced in 15 ml of methanol; 6-methyl-mercaptomethyltetral-2-one (prepared in accordance with EP 96/01238) (1.0 g, 4.7 mmol), dissolved in 10 ml of methanol, was added, and 0.5 g of sodium cyanoborohydride was introduced in portions. The mixture was heated to boiling for 6 hours. After it had cooled down, 25 ml of 1M sodium hydroxide solution were added and the whole was extracted several times with ethyl acetate. After washing with water, drying and evaporating, the residue was purified by column chromatography on silica gel (eluent: methylene chlorie/methanol=9/1).

Yield: 0.56 g (32% of theory); C₂₄H₃₀N₄S₂ (438) MS (m/z): 439 [M+H]⁺.

The compounds below were prepared in an analogous manner using the following cyclic ketones:

Example 4

3-[3-(6-Methyl-1,2,3,4-tetrahydronaphth-2-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole, obtained by the analogous reaction of 6-methyltetral-2-one with 3-(3-aminopropylmercapto)4-methyl-5-phenyl-1,2,4(4H)-triazole.

¹H-NMR (CDCl₃): 1.5-1.6 (mbr, 3H); 2.0 (m, 3H); 2.3 (m, 1H); 2.7-3.0 (m, 7H); 3.4 (t, 3H); 3.6 (s, 3H); 6.8-7.0 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H). C₂₃H₂₈N₄S (392); m.p.: 69-73° C.

Example 5

3-[3-(6-Bromo-1,2,3,4-tetrahydronaphth-2-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole, obtained by the analogous reaction of 6-bromotetral-2-one with 3-(3-aminopropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole.

¹H-NMR (CDCl₃): 2.1 (m, 1H); 2.5-2.9 (m, 5H); 3.2 (m, 1H); 3.3-3.7 (m, 9H); 6.8 (m, 1H); 7.2 (m, 2H); 7.5 (m, 3H); 7.6 (m, 2H). C₂₂H₂₅BrN₄S (457) MS (m/z): 458 [M+H]⁺.

Example 6 3-[3-(1,2,3,4-Tetrahydronaphth-1-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole Hydrochloride

C₂₂H₂₆N₄S (378.5) MS (m/z): 379 [M+H]⁺.

In order to precipitate the hydrochloride, the compound was dissolved in ether/isopropanol, and ethereal hydrochloride acid was then added to the solution while cooling in ice.

C₂₂H₂₆N₄S×HCl; m.p.: 125° C. (decomp.).

Example 7

3-[3-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole, obtained by the analogous reaction of 7-methoxytetral-2-one with 3-(3-Aminopropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole.

¹H-NMR (CDCl₃): 1.5 (m, 1H); 2.0 (m, 3H); 2.5 (m, 1H); 2.8-3.0 (m, 7H); 3.3 (t, 2H); 3.6 (s, 3H); 3.8 (s, 3H); 6.6 (d, 1H); 6.7 (dd, 1H); 7.0 (d, 1H); 7.5 (m, 3H); 7.7 (m, 2H). C₂₃H₂₈N₄OS (408) MS (m/z)=408 [M]⁺.

Example 8

3-[3-(6-Methoxyindan-1-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole, obtained in analogy with Example 1, starting from 6-methoxyindan-1-one.

C₂₂H₂₆N₄OS (394) MS (m/z): 395 [M+H]⁺; ¹H-NMR (DMSO-d₆): 2.1 (m, 3H); 2.4 (m, 1H); 2.75 (m, 1H); 3.0 (m, 3H); 3.3 (t, 2H); 3.6 (s, 3H); 3.8 (s, 3H); 4.7 (t, 1H); 6.5 (s, 2H); 6.9 (dd, 1H); 7.2 (d, 1H); 7.25 (d, 1H); 7.5 (m, 3H); 7.7 (m, 2H).

Example 9

3-[3-(5,6-Dimethoxyindan-1-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole hydrochloride, obtained by the reaction of 5,6-dimethoxyindan-1-one with 3-(3-aminopropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole in analogy With 3B, and Subsequent Precipitation of the Salt With Ethereal HCl.

C₂₃H₂₈N₄O₂S×HCl (461.1); m.p: 201-202° C.; ¹H-NMR (CDCl₃): 2.2-2.5 (m, 4H); 2.8 (m, 1H); 3.2-3.3 (m, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.8 (s, 3H); 3.9 (s, 3H); 4.6 (m, 1H); 6.7 (s, 1H); 7.0 (br, 2H); 7.4 (s, 1H); 7.6 (m, 5H).

Example 10 5-Amino-3-[3-(1,2,3,4-tetrahydronaphth-1-ylamino)propylmercapto-4-methyl-1,2,4(4H)-triazole Hydrochloride

10A Preparation of the Starting Compound

N-(3-Chloropropyl)-1,2,3,4-tetrahydronaphthyl-1-amine 5.0 g (34 mmol) of 1,2,3,4-tetrahydronaphth-1-ylamine were dissolved, together with 6.4 g (40 mmol) of 1-bromo-3-chloropropane and 5.2 g (50 mmol) of triethylamine, in 50 ml of THF and the solution was heated to boiling for 16 h. The solvent was then distilled off and the residue was dissolved in methylene chloride; this solution was washed twice with water, dried and concentrated. The crude product was purified by chromatography on silica gel (eluent:methylene chloride/methanol=97/3), and 3.4 g of a yellowish oil were isolated.

Yield: 3.4 g (44% of theory); ¹H-NMR (CDCl₃): 1.1 (sbr, NH); 1.7-2.0 (m, 6H); 2.6-3.0 (m, 4H); 3.6-3.8 (m, 3H); 7.0-7.4 (m, 4H). C₁₃H₁₈ClN (223.8).

10B Preparation of the End Product

670 mg (3 mmol) of the above-described chlorine compound were dissolved, together with 390 mg (3 mmol) of 5-amino-3-mercapto-4-methyl-1,2,4(4H)-triazole and 72 mg (3 mmol) of lithium hydroxide, in 9 ml of DMF and the solution was stirred at 100° C. for four hours. Water was added and the whole was extracted three times with methyl tert-butyl ether. After the combined organic phases had been dried over sodium sulfate and concentrated, the resulting crude product was purified by chromatography on silica gel (eluent:methylene chloride containing 3-5% methanol).

Yield: 460 mg (48% of theory); C₁₆H₂₃N₅S (317.5).

Precipitation of the hydrochloride in ethereal hydrochloric acid yielded the title compound as a white solid.

C₁₆H₂₃N₅S×HCl (352.9); m.p: 140° C. (decomp.).

Example 11 5-Amino-3-({2-[(1,2,3,4-tetrahydronaphth-1-ylamino)-2-methyl]-prop-2-enyl}mercapto)-4-methyl-1,2,4(4H)-triazole Hydrochloride

11A Preparation of the Starting Compound

1-(3-Chloro-2-methylenepropyl)-1,2,3,4-tetrahydronaphthyl-1-amine

5.0 g (34 mmol) of 1,2,3,4-tetrahydronaphth-1-ylamine were dissolved, together with 5.1 g (41 mmol) of 1,3-dichloro-2-methylenepropane and 5.2 g (51 mmol) of triethylamine, in 50 ml of THF and the solution was heated to boiling for 24 h. The solvent was then distilled off and the residue was dissolved in methylene chloride; this solution was washed twice with water, dried and concentrated. The crude product was purified by chromatography on silica gel (eluent:methylene chloride/methanol=97/3), and 2.6 g of a yellowish oil were isolated.

Yield: 2.6 g (33% of theory); ¹H-NMR (CDCl₃): 1.3 (m, 1H); 1.7-2.0 (m, 4H); 2.6-2.9 (m, 2H); 3.4 (m, 2H); 3.7 (m, 1H); 4.2 (m, 2H); 5.2 (m, 2H); 7.2 (m, 3H); 7.4 (m, 1H).

11B Preparation of the End Product

0.6 g (2.6 mmol) of the above-described chlorine compound was dissolved, together with 0.6 g (2.6 mmol) of 5-amino-3-mercapto-4-methyl-1,2,4(4H)-triazole and 63 mg (2.6 mmol) of lithium hydroxide, in 8 ml of DMF, and the solution was stirred at 100° C. for two hours. Water was then added and the whole was extracted three times with methyl tert-butyl ether. After the combined organic phases had been dried over sodium sulfate and concentrated, the resulting crude product was purified by chromatography on silica gel (eluent:methylene chloride containing 3% methanol).

Yield: 0.55 g (53% of theory) of a colorless oil; C₁₇H₂₃N₅S (329.5) MS (m/z)=331 [M+H]⁺.

The salt was precipitated with ethereal hydrochloric acid at 0° C.

C₁₇H₂₃N₅S×HCl; m.p.: 125° C.

Example 12 3-({2-[(1,2,3,4-Tetrahydronaphth-1-ylamino)-2-methyl]prop-2-enyl}-mercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole Hydrochloride

The compound was obtained by reacting the precursor 11A from Example 11 with 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole.

Yield: 53% of theory. C₂₃H₂₆N₄S×HCl; m.p.: 100° C. (decomp.).

Example 13 3-[3-(6-Bromo-1,2,3,4-tetrahydronaphth-2-ylmethylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole Hydrochloride

The above substance was obtained by methylating the substance from Example 5 with methyl iodide in a manner known per se.

C₂₃H₂₇BrN₄S (471.5) MS (m/z): 470 [M−H]⁺; C₂₃H₂₇BrN₄S×HCl; m.p.: 88° C. (decomp.).

Example 14 3-[3-(6-Methyl-1,2,3,4-tetrahydronaphth-2-ylmethylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

The above substance was obtained by methylating 3-[3-(6-methyl-1,2,3,4-tetrahydronaphth-2-ylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole (Example 4) with methyl iodide in a manner known per se.

¹H-NMR (CDCl₃): 1.9 (m, 2H); 2.3 (s, 3H); 2.5 (mbr, 3H); 2.9 (m, 4H); 3.2 (m, 1H); 3.3-3.5 (m, 4H); 3.6-3.8 (m, 5H); 6.8-7.0 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H). C₂₄H₃₀N₄S (406.6).

Example 15 3-[3-(N-(6-Fluoroindan-1-yl)propylamino)propylmercapto]-4-methyl-5-(2-pyrrolyl)-1,2,4(4H)-triazole Hydrochloride

15A Preparation of the Starting Compounds

15A1 6-Fluoro-1-propylaminoindan

3.27 g (55 mmol) of n-propylamine were initially introduced in 100 ml of methanol, and 15 g (110 mmol) of zinc dichloride were added. 10 g (66 mmol) of 6-fluoro-1-indanone, dissolved in 100 ml of methanol, were then added dropwise. After that, 6.94 g (110 mmol) of sodium cyanoborohydride were added in portions and the reaction mixture was heated to boiling for 3 hours while stirring. After the mixture had cooled down, 200 ml of 1M-NaOH were added and the precipitated salts were filtered off; the filtrate was then extracted with ethyl acetate. After drying and evaporating, the combined organic phases yielded 10.4 g of an oil which was purified by column chromatography on silica gel (eluent:methylene chloride containing 2-5% methanol).

Yield: 4.0 g (31% of theory); ¹H-NMR (CDCl₃): 0.9 (t, 3H); 1.3 (sbr, NH); 1.5 (m, 2H); 1.8 (m, 1H); 2.6 (t, 2H); 2.8 (m, 1H); 3.0 (m, 1H); 4.2 (t, 1H); 6.9 (m, 2H); 7.3 (m, 1H). C₁₂H₁₆FN (193.3) MS (m/z): 193 [M⁺].

15A2 6-Fluoro-1-(3-chloropropyl)-1-propylaminoindan

The above-described product was subsequently reacted as described under 1A.

¹H-NMR (CDCl₃): 0.9 (t, 3H); 1.5 (m, 2H); 1.8-2.1 (m, 4H); 2.3 (t, 2H); 2.5 (m, 2H); 2.7-2.9 (m, 2H); 3.6 (m, 2H); 4.4 (t, 1H); 6.9 (m, 2H); 7.3 (m, 1H). C₁₅H₂₁ClFN (269.8).

15A3 3-Mercapto-4-methyl-5-(pyrrol-2-yl)-1,2,4(4H)-triazole

The triazole was prepared by reacting pyrrole-2-carbonyl chloride with N-methylthiosemicarbazide in pyridine and then cyclizing in an aqueous solution of sodium hydrogen carbonate (in analogy with S. Kubota et al., Chem. Pharm. Bull. 1975,23,955).

¹H-NMR (DMSO-d₆): 3.7 (s, 3H); 6.2 (m, 1H); 6.8 (m, 1H); 7.0 (m, 1H); 11.8 (s, 1H); 14.0 (s, 1H). C₇H₈N₄S (180); m.p.: 200-201° C.

15B Preparation of the End Product

The substance 15 was obtained by reacting 3-mercapto-4-methyl-5-(pyrrol-2-yl)-1,2,4(4H)-triazole with the chlorine base prepared in 15A2, in analogy with Example 1B.

Yield: 73% of theory; C₂₂H₂8FN₅S (413.6); ¹H-NMR (CDCl₃): 0.9 (t, 3H); 1.5 (m, 2H); 1.8-2.0 (m, 3H); 2.1 (m, 1H); 2.3 (t, 2H); 2.5 (m, 2H); 2.7-2.9 (m, 2H); 3.15 (m, 1H); 3.3 (m, 1H); 3.7 (s, 3H); 4.4 (t, 1H); 6.3 (s, 1H); 6.5 (s, 1H); 6.8 (m, 2H); 7.1 (s, 1H); 7.2 (m, 1H); 12.0 (s, 1H).

Precipitation with isopropanolic hydrochloric acid yielded the title compound as a white solid.

C₂₂H₂₈FN₅S×HCl (450.1); m.p.: 120° C. (decomp.).

Example 16 3-[3-(N-(6-Fluoroindan-1-yl)propylamino)propylmercapto]-4-methyl-5-(4-methylthiazol-5-yl)-1,2,4(4H)-triazole Hydrochloride

16A Preparation of the Starting Compounds

4-Methyl-3-mercapto-5-(4-methylthiazol-5-yl)-1,2,4(4H)-triazole

The triazole was prepared by reacting 4-methylthiazole-5-carbonyl chloride with N-methylthiosemicarbazide in pyridine and then cyclizing in an aqueous solution of sodium hydrogencarbonate.

¹H-NMR (DMSO-d₆): 2.4 (s, 3H); 3.4 (s, 3H); 9.2 (s, 1H); 14.1 (s, 1H).

16B Preparation of the End Product

The preparation was effected, in analogy with Example 15, by reacting substance 15A with 3-mercapto-4-methyl-5-(4-methylthiazol-5-yl)-1,2,4(4H)-triazole.

Yield: (70% of theory); C₂₂H₂₈FN₅S₂ (445.6) MS (m/z): 447 [M+H]⁺; ¹H-NMR (CDCl₃): 0.9 (t, 3H); 1.5 (m, 2H); 2.0 (m, 3H); 2.15 (m, 1H); 2.4 (t, 2H); 2.6 (m, 5H); 2.8 (m, 1H); 2.9 (m, 1H); 3.3 (m, 1H); 3.4-3.5 (m, 4H); 4.5 (t, 1H); 6.8 (m, 2H); 7.2 (t, 1H); 9.1 (s, 1H). C₂₂H₂₈FN₅S₂×HCl (482.1); m.p.: 123° C.

The compounds of Examples 17 to 28 were prepared in an analogous manner:

Example 17 5-Amino-3-[3-(N-(8-chloro-1,2,3,4-terahydronaphth-2-yl)propylamino)propylmercapto]-4-methyl-1,2,4(4H)-triazole Example 18 3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

C₂₆H₃₄N₄OS×HCl (487.1); m.p.: 92-95° C.

Example 19 3-[3-(Indan-2-yl-amino)propylmercapto]4-methyl-5-phenyl-1,2,4-(4H)-triazole

¹H-NMR (CDCl₃): 2.0 (m, 2H); 2.2 (sbr, NH), 2.7-2.85 (m, 4H); 3.1 (dd, 2H); 3.3 (t, 2H); 3.5 (s, 3H); 3.7 (t, 1H); 7.1-7.2 (m, 4H); 7.5 (m, 3H); 7.7 (m, 2H). C₂₁H₂₄N₄S (364.5) MS (m/z): 365 [M]⁺.

Example 20 3-[3-(N-(5-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

C₂₃H₂₈N₄OS (409) MS (m/z): 409 [M]⁺.

Example 21 3-[3-(N-(5-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-4-methyl-5-phenyl-1,2,4(4H)-triazole

¹H-NMR (CDCl₃): δ=0.9 (t, 3H); 1.5 (m, 2H); 1.6 (m, 1H); 1.9 (q, 2H); 2.0 (m, 1H); 2.5 (m, 3H); 2.6 (t, 2H); 2.7-3.0 (m, 4H); 3.3 (t, 2H); 3.6 (s, 3H); 3.8 (s, 3H), 6.6 (d, 1H); 6.7 (d, 1H); 7.0 (t, 1H); 7.5 (m, 3H); 7.7 (m, 2H). C₂₆H₃₄N₄OS (450.7).

Example 22 3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-5-tert-butyl-4-methyl-1,2,4(4H)-triazole

C₂₄H₃₈N₄OS (430) MS (m/z): 431 [M+H]⁺.

Example 23 3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-5-methylamino-4-methyl-1,2,4(4H)-triazole

C₂₁H₃₃N₅OS (403.6) MS (m/z): 404.3 [M+H]⁺.

Example 24 3-({2-[(1,2,3,4-Tetrahydronaphth-1-yl-amino)-2-methyl]prop-2-enyl}-mercapto)4-methyl-5-phenyl-1,2,4(4H)-triazole

C₂₃H₂₆N₄OS (390.6).

Example 25 Ethyl-5-{[3-(indan-2-ylamino)propyl]mercapto}-4-methyl-1,2,4(4H)-triazole-3-carboxylate

C₁₈H₂₄N₄O₂S (360).

Treatment with ethereal hydrochloric acid results in the hydrochloride.

C₁₈H₂₄N₄O₂S×HCl (396.9); Melting point: 135-139° C.

Example 26 3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)-propylamino)propylmercapto]-4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-1,2,4(4H)-triazole

¹H-NMR (CDCl₃): δ=0.9 (t, 3H); 1.5 (m, 2H); 1.6 (m, 1H); 2.0 (m, 3H); 2.5 (t, 2H); 2.6 (s, 3H); 2.7-3.0 (m, 7H); 3.4 (t, 2H); 3.5 (s, 3H); 3.8 (s, 3H), 6.6 (s, 1H); 6.7 (d, 1H); 6.9 (d, 1H); 8.9 (s, 1H). C₂₄H₃₃N₅OS₂ (472).

Example 27 3-[3-(N-(5-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)-propylamino)butyl]-4-methyl-5-phenyl-1,2,4(4H)-triazole

¹H-NMR (CDCl₃): δ=0.9 (t, 3H); 1.5 (m, 3H); 2.0 (m, 2H); 2.2 (m, 1H); 2.5 (m, 3H); 2.7 (t, 2H); 2.9 (m, 4H); 3.0 (m, 2H); 3.6 (s, 3H); 3.8 (s, 3H), 6.6 (d, 1H); 6.7 (d, 1H); 7.0 (t, 1H); 7.5 (m, 3H); 7.7 (m, 2H). C₂₇H₃₆N₄O (432.6).

Example 28 3-[3-(N-(7-Methoxy-1,2,3,4-tetrahydronaphth-2-yl)-propylamino)butyl]-4-methyl-5-phenyl-1,2,4(4H)-triazole

¹H-NMR (CDCl₃): δ=0.9 (t, 3H); 1.5 (m, 2H); 1.7 (m, 1H); 1.9 (q, 2H); 2.1 (m, 1H); 2.5 (t, 2H); 2.6 (t, 2H); 2.65-2.8 (m, 8H); 3.1 (s, 1H); 3.5 (s, 3H); 3.8 (s, 3H), 6.5 (s, 1H); 6.6 (dd, 1H); 6.9 (d, 1H); 7.5 (m, 3H); 7.7 (m, 2H). C₂₇H₃₆N₄O (432.6).

The following compounds can be prepared in an analogous way in principle:

Example 29 3-[3-(N-(Indan-2-yl)propylamino)propylmercapto]-4-methyl-5-(pyridin-3-yl)-1,2,4(4H)-triazole Example 30 3-[3-(N-(5-Mercaptomethyl-indan-2-yl)propylamino)propylmercapto]-4-methyl-5-thien-3-yl-1,2,4(4H)-triazole Example 31 4-Cyclopropyl-3-[3-N-(7-methoxy-(1,2,3,4-tetrahydronaphthalin-2-yl)propylamino)propylmercapto]-5-(4-methyl-1,3-thiazol-5-yl)-1,2,4(4H)-triazole Example 32 3-[3-(N-(7-cyano-1,2,3,4-tetrahydronaphth-2-yl)methylamino)propylmercapto]-4-isopropyl-5-(1,3-thiazol-4-yl)-1,2,4(4H)-triazole Hydrochloride Example 33 3-[3-(N-(7-Bromo-1,2,3,4-tetrahydronaphth-2-yl)propylamino)propylmercapto]-4-ethyl-5-(1-methyl-1H-pyrrol-2-yl)-1,2,4(4H)-triazole Example 34 N-{4-[(5-Methoxy-7-methyl)-1,2,3,4-tetrahydronaphthalin-2-yl]-(but-2-enyl)amino]propylmercapto}-4-methyl-5-(3-cyano-phenyl)-1,2,4(4H)-triazole Example 35 3-[7-(N-(5-Fluorindan-2-yl)methylamino)heptylmercapto]-4-propyl-5-(1,3-thiazol-4-yl)-1,2,4(4H)-triazole Example 36 3-[3-(N-(Indan-2-yl)propylamino)butyl]-4-methyl-5-phenyl-1,2,4(4H)-triazole Example 37 3-[3-(N-(5-Methoxyindan-2-yl)propylamino)propoxy]-4-methyl-5-phenyl-1,2,4(4H)-triazole Example 38 N-{4-[(6,7-Dimethoxy-1,2,3,4-tetrahydronaphthalin-2-yl)(propyl)amino]butyl}-4-methyl-5-phenyl-1,2,4(4H)-triazole-3-carboxamide

TABLE 1 Ex. R¹ R² A R⁵ R⁶ R⁷  39 Me 6-Chloro-biphenyl-2— S—(CH₂)₃— n-propyl 6-chloro  40 Me Pyridin-4-yl— S—(CH₂)₃— n-propyl 6-chloro  41 Ethyl N-Methyl-2-Pyrrolyl— CO—CH₂—C(═CH₂)—CH₂ n-propyl 7-methoxy  42 Me Phenyl S—(CH₂)₃— but-2-en-yl 6-iod  43 Me 4-Methylthiazol-5-yl S—(CH₂)₇— n-propyl 6-methyl 7-cyano  44 Me Pyridin-4-yl— S—(CH₂)₃— n-propyl H  45 Me Amino S—(CH₂)₃— n-propyl 6-chloro  46 Me 4-Methylthiazol-5-yl O—(CH₂)₃— n-propyl 7-trifluoromethoxy  47 Me 3-Jod-phenyl S—(CH₂)₃— n-propyl 6-methyl  48 Me 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl 6-bromo  49 Me 4-Methoxyphenyl (CH₂)₄— n-propyl 5-cyano  50 Me N-Methyl-2-Pyrrolyl— S—(CH₂)₃— n-propyl 6-bromo  51 Me Methylamino S—(CH₂)₃— n-propyl 5-cyano  52 Me Phenyl CONH—(CH₂)₅— methyl 6-fluoro  53 Me 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl 6-methyl  54 Me 3-Br-Pyridin-5-yl— S—(CH₂)₃— n-propyl 5-cyano  55 Me Amino S—(CH₂)₃— n-propyl 5-methansulfonyloxy  56 Me 3-Cyano-phenyl CONH—(CH₂)₅— n-propyl 5-fluoro  57 Me Pyridin-4-yl— S—(CH₂)₃— n-propyl 7-methoxy  58 Me 2,5-Di-methyl-furanyl-3— S—(CH₂)₃— n-propyl 6-chloro  59 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 6-bromo  60 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— n-propyl 6-chloro  61 Me 6-Chloro-biphenyl-2— S—(CH₂)₃— n-propyl 6-methyl  62 Me 3-Jod-phenyl S—CH₂—cycProp—CH₂— but-2-en-yl 5-cyano  63 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl 6-bromo  64 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 6-chloro 7-chloro  65 Ethyl Phenyl CO—(CH₂)₃— but-2-en-yl 5-cyano  66 Me 2-Aminothiazol-4yl— S—(CH₂)₃— n-propyl 6-bromo  67 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 6-methyl  68 Me 2-Pyrazinyl— S—CH₂—cycProp—CH₂— methyl 5-nitro  69 Ethyl 2-Pyrazinyl— S—(CH₂)₃— n-propyl 7-methoxy  70 Me 4-Methoxyphenyl O—(CH₂)₃— n-propyl 5-cyano  71 Me 3-Cyano-phenyl O—(CH₂)₃— n-propyl 5-fluoro  72 Me 2-Thienyl S—(CH₂)₃— methyl 5-cyano  73 Me 3-Benzthienyl— S—(CH₂)₃— n-propyl 5-cyano  74 Me 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl 6-bromo  75 Me Cyclohexyl— S—(CH₂)₃— n-propyl 6-methyl  76 Propyl Phenyl S—CH₂—CH═CH—CH₂— methyl 6-fluoro  77 Me 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl 6-methyl  78 Me Phenyl O—(CH₂)₃— but-2-en-yl 5-cyano  79 cycProp 6-Chloro-biphenyl-2— S—(CH₂)₃— n-propyl 7-methoxy  80 Butyl Phenyl O—(CH₂)₃— prop-2en-yl 6-thiomethyl  81 Me Carboxyethyl S—(CH₂)₃— methyl 5-cyano  82 Me N-Methyl-2-Pyrrolyl— S—(CH₂)₃— n-propyl H  83 Butyl 3-Cyano-phenyl O—(CH₂)₃— n-propyl 5-fluoro  84 Me 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl 7-methoxy  85 Me Methylamino S—(CH₂)₃— n-propyl 7-methoxy  86 Me 4-Methylthiazol-5-yl CONH—(CH₂)₄— n-propyl 7-trifluoromethoxy  87 Me 4-Imidazolyl— S—(CH₂)₃— n-propyl H  88 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 7-methansulfonyloxy  89 Me Phenyl S—(CH₂)₃— n-propyl 6-methyl  90 Me Cyclohexyl— S—(CH₂)₃— n-propyl 6-bromo  91 Me Phenyl O—(CH₂)₃— prop-2en-yl 6-thiomethyl  92 Me Phenyl O—(CH₂)₃— methyl 6-fluoro  93 Me Phenyl S—CH₂—cycHex—CH₂—CH₂— methyl 6-fluoro  94 Me Phenyl (CH₂)₄— n-propyl 6-methoxy  95 Ethyl Phenyl S—(CH₂)₇— methyl 6-fluoro  96 Me 2-Pyrazinyl— S—(CH₂)₃— n-propyl 6-chloro  97 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— n-propyl 6-methyl 7-cyano  98 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 7-methoxy  99 Propyl Pyridin-3-yl— S—CH₂—CH═CH—CH₂— n-propyl 6-bromo 7-bromo 100 Me 4-Imidazolyl— S—(CH₂)₃— n-propyl 7-methoxy 101 Me 2-Aminothiazol-4yl— S—(CH₂)₃— n-propyl 7-methoxy 102 Me Phenyl O—(CH₂)₃— n-propyl 7-methansulfonyloxy 103 Me Phenyl S—(CH₂)₃— n-propyl 6-bromo 104 Me Amino S—(CH₂)₃— n-propyl 6-methyl 105 Me 3-Thienyl S—(CH₂)₃— n-propyl 7-methoxy 106 Me N-Methyl-2-Pyrrolyl— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 107 Me Tetrazolyl— S—(CH₂)₃— n-propyl 7-methoxy 108 iProp 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 109 Me Tetrazolyl— S—(CH₂)₃— n-propyl H 110 Ethyl Phenyl SCH₂—C(CH₃)═CH—CH₂— but-2-en-yl 5-cyano 111 Me 2,5-Di-methyl-furanyl-3— S—(CH₂)₃— n-propyl H 112 Me tert.Butyl S—(CH₂)₃— methyl 5-cyano 113 Me 4-Jod-phenyl S—(CH₂)₃— n-propyl 7-methoxy 114 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl 5-cyano 115 Me 4-Methoxyphenyl S—CH₂—cycProp—(CH₂)₂— prop-2en-yl 6-thiomethyl 116 Me Phenyl S—CH₂—CH═CH—CH₂— n-propyl 7-methansulfonyloxy 117 Me 2-Aminothiazol-4yl— S—(CH₂)₃— n-propyl 5-cyano 118 cycProp 5-Methyl imidazol-4-yl— S—(CH₂)₃— prop-2en-yl 7-methansulfonyloxy 119 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— prop-2en-yl 7-methansulfonyloxy 120 nHexyl 4-Methoxyphenyl S—(CH₂)₃— n-propyl 6-chloro 121 Me 2-Thienyl S—(CH₂)₃— n-propyl H 122 Me Phenyl COO—(CH₂)₄— n-propyl 7-methansulfonyloxy 123 Me cycPropyl S—(CH₂)₃— methyl 5-cyano 124 Me 4-Imidazolyl— S—(CH₂)₃— n-propyl 5-methansulfonyloxy 125 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 5-cyano 126 Butyl 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl 7-methansulfonyloxy 127 iProp Cyclohexyl— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 128 Me Tetrazolyl— S—(CH₂)₃— n-propyl 6-bromo 129 Propyl Methylamino S—(CH₂)₃— methyl 5-cyano 130 Me Amino S—(CH₂)₃— n-propyl 6-bromo 131 Me 3-Jod-phenyl S—(CH₂)₃— methyl 5-cyano 132 Me 2-Thienyl S—(CH₂)₃— n-propyl 6-chloro 133 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 6-bromo 134 Me 2-Thienyl S—(CH₂)₃— n-propyl 5-cyano 135 Ethyl 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl 7-methoxy 136 Me 2-Pyrazinyl— (CH₂)₂—CH(CH₃)—CH₂—CH₂— n-propyl 6-methyl 137 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl 6-methyl 138 Me N-Propyl-tetrazolyl— S—(CH₂)₃— n-propyl H 139 Me 4-Imidazolyl— S—(CH₂)₃— n-propyl 6-methyl 140 Me 2-Pyrazinyl— O—(CH₂)₃— n-propyl 6-methyl 141 Me 2-Pyrazinyl— S—(CH₂)₃— n-propyl 6-bromo 142 Ethyl Phenyl CO—(CH₂)₃— prop-2en-yl 6-chloro 7-chloro 143 Me Pyridin-4-yl— S—(CH₂)₃— n-propyl 5-methansulfonyloxy 144 Me 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl 6-chloro 145 Me 3-Jod-phenyl (CH₂)₂—CH(CH₃)—CH₂—CH₂— n-propyl 5-cyano 146 Me 3-Benzthienyl— S—(CH₂)₃— n-propyl 5-methansulfonyloxy 147 Phenyl Phenyl S—(CH₂)₃— n-propyl 6-methoxy 148 Me 2-Aminothiazol-4yl— S—(CH₂)₃— n-propyl 6-methyl 149 Me Pyridin-3-yl— S—(CH₂)₃— n-propyl 7-methoxy 150 Me 3-Br-Pyridin-5-yl— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 151 Me 4-Methoxyphenyl COO—(CH₂)₃— n-propyl 5-cyano 152 Me 4-Imidazolyl— S—(CH₂)₃— n-propyl 5-cyano 153 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 154 Me 4-Imidazolyl— S—(CH₂)₃— n-propyl 6-chloro 155 Me Trifluoromethyl S—(CH₂)₃— methyl 5-cyano 156 Me Tetrazolyl— S—(CH₂)₃— n-propyl 5-cyano 157 Me Pyridin-3-yl— CONH—(CH₂)₄— n-propyl 6-bromo 158 Me Pyridin-3-yl— O—(CH₂)₃— n-propyl 6-bromo 159 Me Pyridin-4-yl— S—(CH₂)₃— n-propyl 5-cyano 160 Me N-Propyl-tetrazolyl— S—(CH₂)₃— n-propyl 5-cyano 161 Me Methylamino S—(CH₂)₃— n-propyl 6-bromo 162 Me N-Propyl-tetrazolyl— S—(CH₂)₃— n-propyl 6-bromo 163 Me Phenyl S—CH₂—cycHex—CH₂— n-propyl 7-trifluoromethoxy 164 Phenyl 2-Pyrazinyl— S—(CH₂)₃— n-propyl 6-ethyl 165 Me 2-Thienyl S—(CH₂)₃— n-propyl 6-methyl 166 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— n-propyl 7-methoxy 167 Me 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl H 168 Me 4-Methoxyphenyl S—CH₂—C(═CH₂)—CH₂ n-propyl 5-cyano 169 Me 2-Thienyl S—(CH₂)₃— n-ethyl 6-methxoxy 7-methoxy 170 Me 3-Br-Pyridin-5-yl— S—(CH₂)₃— n-propyl 6-bromo 171 Me 2-Thienyl O—(CH₂)₃— n-propyl 6-chloro 172 Me 2-Pyrazinyl— S—(CH₂)3— n-propyl 6-methyl 173 Me 4-Methoxyphenyl S—(CH₂)₃— n-propyl 7-methoxy 174 cycProp 2-Pyrazinyl— S—(CH₂)₃— prop-2en-yl 6-carboxamid 175 Me Amino S—(CH₂)₃— n-propyl 7-methoxy 176 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl 7-methansulfonyloxy 177 Me 3-Br-Pyridin-5-yl— S—(CH₂)₃— n-propyl H 178 Me 2-Thienyl S—CH₂—C(═CH₂)—CH₂ n-propyl 6-chloro 179 Me Phenyl COO—(CH₂)₄— n-propyl 6-methoxy 180 Butyl Tetrazolyl— S—(CH₂)₃— methyl 5-cyano 181 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 6-chloro 182 Me 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl H 183 Me 2,5-Di-methyl-furanyl-3— S—(CH₂)₃— n-propyl 5-cyano 184 Me N-Methyl-2-Pyrrolyl— O—(CH₂)₃— n-propyl 7-methoxy 185 iProp 3-Br-Pyridin-5-yl— S—(CH₂)₃— n-propyl 6-chloro 7-chloro 186 Me 3-Br-Pyridin-5-yl— S—(CH₂)₃— n-propyl 6-methyl 187 Me Cyclohexyl— S—(CH₂)₇— n-propyl 6-chloro 7-chloro 188 Me N-Methyl-2-Pyrrolyl— S—(CH₂)₃— n-propyl 7-methoxy 189 Me 3-Jod-phenyl COO—(CH₂)₄— n-propyl 5-cyano 190 Me 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl 5-cyano 191 Me 2-Pyrazinyl— S—CH₂—CH═CH—CH₂— n-propyl 6-methyl 192 Me 3-Jod-phenyl S—(CH₂)₃— n-propyl 6-chloro 193 Me Cyclohexyl— S—(CH₂)₃— n-propyl 5-cyano 194 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl H 195 Me Pyridin-3-yl— S—(CH₂)₃— n-propyl 5-cyano 196 Me N-Propyl-tetrazolyl— S—(CH₂)₃— n-propyl 6-chloro 197 Ethyl 3-Jod-phenyl S—(CH₂)₃— H 6-chloro 7-chloro 198 Me 3-Jod-phenyl O—(CH₂)3— n-propyl 5-cyano 199 Butyl Phenyl O—(CH₂)₃— methyl 6-fluoro 200 Me Methylamino S—(CH₂)₃— n-propyl H 201 Me Methylamino S—(CH₂)₃— n-propyl 6-chloro 202 Me Phenyl S—CH₂—cycHex—CH₂—CH₂— n-propyl 5-fluoro 203 Me 3-Jod-phenyl S—CH₂—C(═CH₂)—CH₂ n-propyl 5-cyano 204 Me 3-Benzthienyl— S—(CH₂)3— n-propyl 6-methyl 205 Me Pyridin-4-yl— S—(CH₂)₃— n-propyl 6-methyl 206 Me Amino S—(CH₂)₃— n-propyl 5-cyano 207 Me N-Methyl-2-Pyrrolyl— S—(CH₂)₃— n-propyl 6-chloro 208 Me 2-Thienyl COO—(CH₂)₄— n-propyl 6-chloro 209 Me 3-Benzthienyl— S—(CH₂)₃— n-propyl 6-bromo 210 Me N-Methyl-2-Pyrrolyl— S—(CH₂)₃— n-propyl 6-methyl 211 Me Phenyl S—CH₂—cycProp—CH₂— H 6-bromo 212 Me N-Propyl-tetrazolyl— S—(CH₂)₃— n-propyl 5-methansulfonyloxy 213 Me 2-Pyrazinyl— S—(CH₂)₃— n-propyl 7-methoxy 214 Me 3-Benzthienyl— S—(CH₂)₃— n-propyl 6-chloro 215 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 6-methyl 216 Me Methyl S—(CH₂)₃— prop-2en-yl 7-methansulfonyloxy 217 Me Tetrazolyl— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 218 Me 6-Chloro-biphenyl-2— S—(CH₂)₃— methyl 5-cyano 219 Me 4-Methylthiazol-5-yl S—(CH₂)₃— methyl 5-cyano 220 Me 2-Thienyl S—CH₂—C(═CH₂)—CH₂ n-propyl 6-chloro 221 Me 3-Benzthienyl— S—(CH₂)₃— methyl 7-methoxy 222 Me 4-Methoxyphenyl S—(CH₂)₃— n-propyl 5-cyano 223 Butyl 2-Thienyl S—(CH₂)₃— n-propyl 7-methansulfonyloxy 224 Me Methylamino S—(CH₂)₃— n-propyl 7-methansulfonyloxy 225 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 7-methoxy 226 Me Phenyl S—(CH₂)₃— n-propyl H 227 Me Pyridin-3-yl— S—(CH₂)₃— n-propyl 6-methyl 228 Me Phenyl S—(CH₂)₃— prop-2en-yl 7-methansulfonyloxy 229 Ethyl Phenyl S—CH₂—C(CH₃)═CH—CH₂— prop-2en-yl 6-chloro 7-chloro 230 Me N-Propyl-tetrazolyl— S—(CH₂)₃— n-propyl 6-methyl 231 Me Dimethylamino S—(CH₂)₃— methyl 5-cyano 232 Me 2-Aminothiazol-4yl— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 233 Me 2,5-Di-methyl-furanyl-3— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 234 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— methyl 5-cyano 235 Me 4-Methoxyphenyl S—CH₂—cycProp—(CH₂)₂— but-2-en-yl 5-methoxy 236 Me 6-Chloro-biphenyl-2— S—(CH₂)₃— n-propyl 5-cyano 237 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl H 238 Me 4-Methoxyphenyl S—(CH₂)₃— n-propyl 5-methansulfonyloxy 239 nHexyl 2-Pyrazinyl— S—(CH₂)₃— prop-2en-yl 7-methansulfonyloxy 240 Me 3-Jod-phenyl S—(CH₂)₃— n-propyl 6-bromo 241 Me Pyridin-3-yl— S—(CH₂)₃— methyl 5-cyano 242 Me N-Propyl-tetrazolyl— S—(CH₂)₃— n-propyl 7-methoxy 243 Me 3-Br-Pyridin-5-yl— S—(CH₂)₃— n-propyl 7-methoxy 244 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 5-cyano 245 Me Phenyl O—(CH₂)₃— prop-2en-yl 6-thiomethyl 246 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— n-propyl 5-cyano 247 Ethyl Phenyl S—(CH₂)₆— n-propyl 6-methoxy 248 Me Pyridin-4-yl— S—(CH₂)₃— n-propyl 6-bromo 249 cycProp 3-Pyrrolyl S—(CH₂)₃— prop-2en-yl 7-methansulfonyloxy 250 Me Benzyl S—(CH₂)₃— methyl 5-cyano 251 Propyl 4-Methylthiazol-5-yl S—CH₂—CH═CH—CH₂— n-propyl 7-trifluoromethoxy 252 Me Phenyl O—(CH₂)₃— but-2-en-yl 5-cyano 253 Me 6-Chloro-biphenyl-2— S—(CH₂)₃— n-propyl 6-bromo 254 Me 3-Jod-phenyl S—(CH₂)₃— n-propyl 5-cyano 255 Me Phenyl O—(CH₂)₃— prop-2en-yl 6-chloro 256 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl 7-methoxy 257 Me 2-Pyrazinyl— S—(CH₂)₃— n-propyl H 258 Me Cyano S—(CH₂)₃— methyl 5-cyano 259 Me 4-Methoxyphenyl S—(CH₂)3— n-propyl 6-bromo 260 Ethyl Phenyl S—CH₂—C(CH₃)═CH—CH₂— prop-2en-yl 6-thiomethyl 261 Ethyl Phenyl S—(CH₂)₆— but-2-en-yl 5-cyano 262 Me 2-Thienyl S—(CH₂)₃— prop-2en-yl 5-methansulfonyloxy 263 Me 3-Benzthienyl— S—(CH₂)₃— n-propyl H 264 Me Pyridin-3-yl— S—(CH₂)₃— n-propyl 6-bromo 265 Me Cyclohexyl— S—(CH₂)₃— n-propyl H 266 cycProp Cyclohexyl— S—(CH₂)₃— prop-2en-yl 7-methansulfonyloxy 267 Ethyl 3-Pyrrolyl S—(CH₂)₃— n-propyl 7-methoxy 268 Me 2-Pyrazinyl— S—(CH₂)₃— n-propyl 5-cyano 269 Me Phenyl O—(CH₂)₃— but-2-en-yl 5-cyano 270 Me 2,5-Di-methyl-furanyl-3— S—(CH₂)3— n-propyl 7-methoxy H 271 cycProp Oxadiazol-2-yl S—(CH₂)₃— n-propyl 7-methoxy 272 Me Phenyl S—(CH₂)3— n-propyl 6-chloro 273 Me Methylamino S—(CH₂)₃— n-propyl 6-methyl 274 Me Phenyl S—(CH₂)₃— n-propyl 5-methansulfonyloxy 275 Me 2-Aminothiazol-4yl— S—(CH₂)₃— n-propyl H 276 Me N-Methyl-2-Pyrrolyl— S—(CH₂)3— n-propyl 5-cyano 277 Me 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl 6-chloro 278 Me 6-Chloro-biphenyl-2— S—(CH₂)3— n-propyl 7-methoxy 279 nHexyl 3-Cyano-phenyl S—(CH₂)₃— prop-2en-yl 6-chloro 280 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 6-chloro 281 Me 3-Jod-phenyl S—(CH₂)₃— n-propyl 7-methansulfonyloxy 282 Me 3-Jod-phenyl S—(CH₂)₃— n-propyl H 283 Me 5-Methyl imidazol-4-yl— S—(CH₂)₃— H 7-methansulfonyloxy 284 Me 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl 6-trifluoromethoxy 285 Me Cyclohexyl— S—(CH₂)₃— n-propyl 6-chloro 286 Me 2-Pyrazinyl— S—(CH₂)₇— but-2-en-yl 7-iod 8-chloro 287 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— n-propyl H 288 Ethyl Phenyl S—(CH₂)₇— prop-2en-yl 6-thiomethyl 289 Me Cyclohexyl— S—(CH₂)3— n-propyl 7-methoxy 290 Me N-Methyl-2-Pyrrolyl— CONH—(CH₂)4— n-propyl 7-methoxy 291 Ethyl Phenyl (CH₂)₄— but-2-en-yl 5-cyano 292 Me 2,5-Di-methyl-furanyl-3— S—(CH₂)₃— n-propyl 6-bromo 293 Me Pyridin-3-yl— S—(CH₂)₃— n-propyl 6-chloro 294 Ethyl 2,5-Di-methyl-furanyl-3— S—(CH₂)₃— methyl 5-cyano 295 Me Cyclohexyl— S—(CH₂)₃— methyl 5-cyano 296 Me 6-Chloro-biphenyl-2— S—(CH₂)₃— n-propyl 6-methyl 7-methyl 297 Me 4-Methoxyphenyl S—(CH₂)3— n-propyl H 298 Me Tetrazolyl— S—(CH₂)₃— n-propyl 6-methyl 299 Me Tetrazolyl— S—(CH₂)3— n-propyl 6-chloro 300 Me Phenyl (CH₂)₂—CH(CH₃)—CH₂—CH₂— n-propyl 7-methansulfonyloxy 301 Me Amino S—(CH₂)₃— n-propyl H 302 Me 2-Thienyl S—(CH₂)₃— n-propyl 6-bromo 303 Me 6-Chloro-biphenyl-2— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 304 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl H 305 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— n-propyl 6-methyl 306 Me Pyridin-3-yl— S—(CH₂)₃— n-propyl H 307 Me 4-Methylthiazol-5-yl S—(CH₂)₃— prop-2en-yl 7-methansulfonyloxy 308 Me 5-Methyl imidazol-4-yl— S—(CH₂)₃— n-propyl 5-cyano 309 Me 2,5-Di-methyl-furanyl-3— S—(CH₂)₃— n-propyl 6-methyl 310 Propyl 3-Cyano-phenyl S—CH₂—C(CH₃)═CH—CH₂— n-propyl 5-fluoro 311 Me 4-Methoxyphenyl S—(CH₂)₃— n-propyl 6-methyl 312 Ethyl 3-Cyano-phenyl S—(CH₂)₈— n-propyl 5-fluoro 313 Me 2-Pyrazinyl— COO—(CH₂)₄— n-propyl 6-methyl 314 Me Phenyl S—(CH₂)₃— n-propyl 5-cyano 315 Me Pyridin-3-yl— S—(CH₂)₃— n-propyl 7-methansulfonyloxy 316 Me 4-Imidazolyl— S—(CH₂)₃— n-propyl 6-bromo 317 iProp 2-Aminothiazol-4yl— S—(CH₂)₃— n-propyl 6-chloro 318 nHexyl 3-Pyrrolyl S—(CH₂)₃— n-propyl 7-methansulfonyloxy 319 Me 2-Me-4-Oxazolyl— S—(CH₂)₃— n-propyl 6-bromo 320 cycProp 3-Br-Pyridin-5-yl— S—(CH₂)3— prop-2en-yl 7-methansulfonyloxy 321 Me 6-Chloro-biphenyl-2— S—(CH₂)3— n-propyl H 322 Me Oxadiazol-2-yl S—(CH₂)3— methyl 5-cyano

TABLE 2 Ex. R¹ R² A R⁵ R⁶ R⁷ 323 Ethyl 2,5-Di-methyl-fura- S—(CH₂)₃— n-propyl 5-bromo nyl-3- 324 Me 4-Methylthiazol-5-yl S—(CH₂)₇— n-propyl 5-methyl 7-chloro 325 Ethyl N-Methyl-2-Pyrrolyl- S—(CH₂)₃— n-Propenyl 5-bromo 326 Me N-Methyl-2-Pyrrolyl- S—(CH₂)₃— n-propyl 6-methoxy 327 Me 3-Benzthienyl- S—(CH₂)₃— methyl 6-methoxy 328 cycProp Cyclohexyl- S—(CH₂)₆— prop-2en-yl 6-methansulfonyloxy 329 Ethyl 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl 5-bromo 330 Ethyl 3-Benzthienyl- S—(CH₂)₃— n-propyl 5-bromo 331 Ethyl 2,5-Di-methyl-fura- S—(CH₂)₃— methyl 4-cyano nyl-3- 332 Me Phenyl (CH₂)₂—CH(CH₃)—CH₂—CH₂— n-propyl 6-methansulfonyloxy 333 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl 6-methansulfonyloxy 334 Me Pyridin-4-yl S—(CH₂)₃— n-propyl 4-cyano 335 Me 2,5-Di-methyl-fura- S—(CH₂)₃— n-propyl 6-methansulfonyloxy nyl-3- 336 Me 2-Pyrazinyl- (CH₂)₂—CH(CH₃)—CH₂—CH₂— n-propyl 5-methyl 337 Me Methylamino S—(CH₂)₃— n-propyl 6-methoxy 338 Me Phenyl O—(CH₂)₃— but-2-en-yl 4-cyano 339 Me 3-Cyano-phenyl S—(CH₂)₃— methyl 6-methoxy 340 Me 3-Jod-phenyl COO—(CH₂)₄— n-propyl 4-cyano 341 Propyl 3-Cyano-phenyl S—CH₂—C(CH₃)═CH—CH2— n-propyl 4-fluoro 342 Me 2-Me-4-Oxazolyl- S—(CH₂)3— n-propyl 6-methoxy 343 Me N-Methyl-2-Pyrrolyl- S—(CH₂)₃— n-propyl H 344 Me 4-Imidazolyl- S—(CH₂)₃— n-propyl 5-methyl 345 Ethyl Phenyl S—CH₂—C(CH₃)═CH—CH₂— prop-2en-yl 5-thiomethyl 346 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 4-cyano 347 Me 2-Pyrazinyl- S—(CH₂)₃— n-propyl 5-chloro 348 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 5-methyl 349 Me 2-Pyrazinyl- S—(CH₂)₇— but-2-en-yl 6-iod 350 Me 2-Pyrazinyl- COO—(CH₂)₄— n-propyl 5-methyl 351 Me 5-Methyl imida- S—(CH₂)₃— n-propyl 5-chloro zol-4-yl- 352 Me Pyridin-4-yl- S—(CH₂)₃— n-propyl H 353 Me 2-Pyridin-3-yl S—(CH₂)3— n-propyl 5-chloro 354 Me N-Methyl-2-Pyrrolyl- S—(CH₂)₃— n-propyl 6-methansulfonyloxy 355 Me 2-Thienyl S—(CH₂)₃— methyl 4-cyano 356 Me Phenyl O—(CH₂)₃— prop-2en-yl 5-chloro 357 Me Tetrazolyl- S—(CH₂)₃— n-propyl 4-cyano 358 Me Phenyl S—(CH₂)₃— n-propyl 5-chloro 359 Me Pyridin-3-yl- S—(CH₂)₃— n-Propenyl 5-methyl 360 Me 3-Thienyl S—(CH₂)₃— n-propyl 6-methoxy 361 Me Phenyl S—CH₂-cycHex-CH₂— n-propyl 6-trifluoromethoxy 362 Ethyl Phenyl CO—(CH₂)₃— but-2-en-yl 4-cyano 363 Me 3-Br-Pyridin-5-yl- S—(CH₂)₃— n-propyl 6-methansulfonyloxy 364 Me Tetrazolyl- S—(CH₂)₃— n-propyl H 365 Me 2-Thienyl S—(CH₂)₃— n-propyl 4-cyano 366 Me 4-Methoxyphenyl (CH₂)₄— n-propyl 4-cyano 367 Me Phenyl O—(CH₂)₃— n-propyl 6-methansulfonyloxy 368 Ethyl 3-Pyrrolyl S—(CH₂)₃— n-propyl 6-methoxy 6-chloro 369 Me Phenyl S—(CH₂)₃— prop-2-en-yl H 370 Butyl 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl 6-methansulfonyloxy 371 Me Pyridin-3-yl- O—(CH₂)₃— n-propyl 5-bromo 372 Me 4-Methylthiazol-5-yl S—(CH₂)₃— methyl 4-cyano 373 Me 2-Pyrazinyl- S—CH₂-cycProp-CH₂— methyl 4-nitro 374 Me 2-Pyrazinyl- S—(CH₂)3— n-propyl 5-methyl 6-methyl 375 Me Amino S—(CH₂)₃— n-propyl H 376 Me Methylamino S—(CH₂)₃— n-propyl H 377 Butyl 2-Thienyl S—(CH₂)₃— n-propyl 6-methansulfonyloxy 378 Ethyl Amino S—(CH₂)₃— n-propyl 5-bromo 379 Me 4-Methoxyphenyl S—CH₂cycProp-(CH₂)₂— but-2-en-yl 4-methoxy 380 iProp Cyclohexyl S—(CH₂)₃— n-propyl 6-methansulfonyloxy 381 Me 4-Methoxyphenyl S—(CH₂)₃— n-propyl 4-cyano 382 Me N-Propyl-tetrazolyl- S—(CH₂)₃— n-propyl H 383 Me 2-Thienyl COO—(CH₂)₄— n-propyl 5-chloro 384 Me 2-Thienyl S—(CH₂)₃— n-ethyl 5-methxoxy 385 Ethyl 2-Thienyl S—(CH₂)₃— n-propyl 5-bromo 386 cycProp 3-Br-Pyridin-5-yl- S—(CH₂)₆— prop-2en-yl 6-methansulfonyloxy 387 Propyl Methylamino S—(CH₂)₃— methyl 4-cyano 388 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 6-methansulfonyloxy 389 Ethyl 3-Pyrazinyl- S—(CH₂)₃— n-propyl 6-methoxy 390 Me Pyridin-3-yl S—(CH₂)₃— n-propyl 6-methoxy 391 Ethyl 4-Imidazolyl- S—(CH₂)₃— n-propyl 5-bromo 392 Me Phenyl O—(CH₂)₃— but-2-en-yl 4-cyano 393 Me Phenyl S—(CH₂)₃— n-propyl H 394 Me 3-Jod-phenyl S—(CH₂)₃— H 4-cyano 395 nHexyl 3-Pyrrolyl S—(CH₂)3— n-propyl 6-methansulfonyloxy 396 Me Phenyl CONH—(CH₂)₅— methyl 5-fluoro 397 Ethyl Phenyl (CH₂)₄— but-2-en-yl 4-cyano 398 Me Amino S—(CH₂)₃— n-propyl 5-chloro 399 cycProp 3-Pyrrolyl S—(CH₂)₆— prop-2en-yl 6-methansulfonyloxy 6-chloro 400 Ethyl Phenyl S—CH₂)₇— methyl 5-fluoro 401 Me Phenyl S—(CH₂)₃— n-propyl 5-methyl 402 Me 4-Methoxyphenyl S—CH₂-cycProp-(CH₂)₂— prop-2en-yl 5-thiomethyl 403 Ethyl 3-Jod-phenyl S—(CH₂)₃— H 5-chloro 6-chloro 404 Ethyl N-Methyl-2-Pyrrolyl- CO—CH₂—C(═CH₂)—CH₂ n-propyl 6-methoxy 405 Me 4-Methoxyphenyl O—(CH₂)₃— n-propyl 4-cyano 406 Ethyl Oxadiazol-2-yl S—(CH₂)₃— n-Propenyl 5-bromo 407 Me 3-Jod-phenyl (CH₂)₂—CH(CH₃)—CH₂—CH₂— n-propyl 4-cyano 408 Me Phenyl O—(CH₂)₃— prop-2en-yl 5-thiomethyl 409 Me 2-Pyrazinyl- S—(CH₂)₃— n-propyl 4-cyano 410 Me 3-Jod-phenyl S—(CH₂)₃— n-propyl H 411 Me N-Methyl-2-Pyrrolyl- CONH—(CH₂)₄— n-propyl 6-methoxy 412 Me 3-Jod-phenyl S—(CH₂)₃— n-Propenyl 5-methyl 413 Me N-Methyl-2-Pyrrolyl- S—(CH₂)₃— n-propyl 4-cyano 414 Me Phenyl S—(CH₂)₃— n-propyl 4-cyano 415 Ethyl Phenyl S—(CH₂)₆— n-propyl 5-methoxy 6-chloro 416 Ethyl Phenyl S—(CH₂)₆— but-2-en-yl 4-cyano 417 Me Cyclohexyl- S—(CH₂)₇— n-propyl 5-chloro 6-chloro 418 Me Phenyl O—(CH₂)₃— prop-2en-yl 5-thiomethyl 419 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl H 420 Me N-Propyl-tetrazolyl- S—(CH₂)₃— n-propyl 5-methyl 421 Me Oxadiazol-2-yl S—(CH₂)₃— methyl 4-cyano 422 Me Cyclohexyl- S—(CH₂)3— n-propyl 4-cyano 423 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— n-propyl 4-cyano 424 Me Methylamino S—(CH₂)₃— n-propyl 5-chloro 425 Me 2-Pyrazinyl- s—CH₂—CH═CH—CH₂— n-propyl 5-methyl 426 cycProp 6-Chloro-biphenyl-2- S—(CH₂)₃— n-propyl 6-methoxy 427 Ethyl 3-Cyano-phenyl S—(CH₂)₈— n-propyl 4-fluoro 6-chloro 428 Ethyl Phenyl S—(CH₂)₃— n-propyl 5-bromo 429 Butyl Phenyl O—(CH₂)₃— methyl 5-fluoro 430 Me 4-Imidazolyl- S—(CH₂)₃— methyl 6-methoxy 431 Ethyl Phenyl S—CH₂—C(CH₃)═CH—CH₂— but-2-en-yl 4-cyano 432 Me Phenyl COO—(CH₂)₄— n-propyl 6-methanesulfonyloxy 433 Me 3-Jod-phenyl S—(CH₂)₃— methyl 4-cyano 434 Me 2,5-Di-methyl-fura- S—(CH₂)₃— n-propyl 4-cyano nyl-3- 435 Me 4-Methoxyphenyl S—(CH₂)₃— n-propyl 5-methyl 436 Me Tetrzolyl- S—(CH₂)₃— n-propyl 6-methoxy 437 Me 3-Br-Pyridin-5-yl S—(CH₂)₃— n-propyl 4-cyano 6-methyl 438 Me Tetrazolyl- S—(CH₂)₃— n-Propenyl 5-methyl 439 Me Pyridin-3-yl- S—(CH₂)3— n-propyl 4-cyano 440 Me 3-Br-Pyridin-5-yl- S—(CH₂)₃— n-propyl 5-methyl 441 Me 4-Methoxyphenyl S—(CH₂)₃— n-propyl 4-methansulfonyloxy 442 Me 3-Benzthienyl- S—CH₂)3— n-propyl 5-methyl 443 Me Pyridin-4-yl- S—(CH₂)₃— methyl 6-methoxy 444 Me 3-Jod-phenyl S—CH₂-cycProp-CH2- but-2-en-yl 4-cyano 445 Me 2-Pyrazinyl- S—(CH₂)₃— n-propyl H 446 Me Phenyl S—CH₂-cycProp-CH2- H 5-bromo 447 Me Phenyl O—(CH₂)₃— methyl 5-fluoro 448 cycProp 2-Pyrazinyl- S—(CH₂)₃— prop-2en-yl 5-iod 449 Me 3-Cyano-phenyl CONH—(CH₂)₅— n-propyl 4-fluoro 450 nHexyl 2-Pyrazinyl- S—(CH₂)₃— prop-2en-yl 6-methansulfonyloxy 451 Me Phenyl S—CH₂—CH═CH—CH₂— n-propyl 6-methansulfonyloxy 452 iProp 3-Br-Pyridin-5-yl- S—(CH₂)₃— n-propyl 5-chloro 453 Me Phenyl O—(CH₂)₃— but-2-en-yl 4-cyano 454 Me 2-Thienyl S—CH₂—C(═CH₂)—CH₂ n-propyl 5-chloro 455 Me Pyridin-3-yl- S—(CH₂)₃— n-propyl 6-methansulfonyloxy 456 Et Phenyl S—(CH₂)₃— n-propyl 5-methoxy 6-methoxy 457 Propyl Pyridin-3-yl S—CH₂—CH═CH—CH₂— n-propyl 5-bromo 458 Butyl Tetrazolyl- S—(CH₂)₃— methyl 4-cyano 459 Me 3-Br-Pyridin-5-yl- S—(CH₂)₃— n-propyl 6-methoxy 460 Me 2-Pyrazinyl- S—(CH₂)₃— n-propyl 5-methyl 461 Me Pyridin-3-yl- S—(CH₂)₃— n-propyl H 462 Me 3-Benzthienyl- S—CH₂)3— n-propyl 5-chloro 463 Me Phenyl S—CH₂-cycHex-CH₂—CH₂— n-propyl 4-fluoro 464 Butyl 3-Cyano-phenyl O—(CH₂)₃— n-propyl 4-fluoro 465 Me 6-Chloro-biphenyl-2- S—(CH₂)₃— n-propyl 5-fluoro 466 Ethyl 3-Jod-phenyl S—(CH₂)₃— n-Propenyl 5-bromo 467 Ethyl 2-Me-4-Oxazolyl- S—(CH₂)₃— n-Propenyl 5-bromo 468 Me Oxadiazol-2-yl S—(CH₂)₃— n-propyl 5-chloro 469 Propyl Phenyl S—CH₂—CH═CH—CH₂— methyl 5-fluoro 470 Me 3-Jod-phenyl S—(CH₂)₃— n-propyl 6-methansulfonyloxy 471 Butyl Phenyl O—(CH₂)₃— prop-2en-yl 5-thiomethyl 472 nHexyl 3-Cyano-phenyl S—CH₂—CH═CH—CH₂— prop-2en-yl 5-chloro 473 Me 5-Methyl imida- S—(CH₂)₃— n-propyl 4-cyano zol-4-yl- 474 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— n-propyl 5-chloro 475 Me 4-Methoxyphenyl S—(CH₂)₃— n-propyl H 476 nHexyl 4-Methoxyphenyl S—(CH₂)₃— n-propyl 5-chloro 477 Me 2-Pyrazinyl- S—(CH₂)₃— n-propyl 6-methoxy 478 Me 3-Jod-phenyl S—CH₂—C(CH═CH₂)—CH₂ n-Propenyl 4-cyano 479 Me 4-Imidazolyl- S—(CH₂)₃— H 4-cyano 480 Ethyl 5-Methyl imida- S—(CH₂)₃— n-propyl 6-methoxy zol-4-yl- 481 Me Phenyl COO—(CH₂)₄— n-propyl 5-methoxy 482 Me 4-Methylthiazol-5-yl CONH—(CH₂)₄— n-propyl 6-trifluoromethoxy 483 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 6-methoxy 484 Me 4-Imidazolyl- S—(CH₂)₃— n-propyl H 485 Me 2-Thienyl O—(CH₂)₃— n-propyl 5-chloro 486 Me 2-Thienyl S—(CH₂)₃— n-propyl 5-chloro 487 Ethyl Phenyl S—CH₂—C(CH₃)═CH—CH₂— prop-2en-yl 5-chloro 488 Me 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl 5-chloro 489 Me Pyridin-4-yl- S—(CH₂)₃— n-propyl 5-fluoro 490 Me N-Propyl-tetrazolyl- S—(CH₂)₃— methyl 6-methoxy 491 Ethyl Phenyl S—(CH₂)₇— prop-2en-yl 5-thiomethyl 492 cycProp Oxadiazol-2-yl S—(CH₂)₃— n-propyl 6-methoxy 493 Me 4-Imidazolyl- S—(CH₂)3— n-propyl 5-chloro 494 Me 4-Methylthiazol-5-yl S—(CH₂)₃— n-propyl H 495 Me N-Methyl-2-Pyrrolyl- S—(CH₂)₃— prop-2en-yl 5-methyl 496 Me Phenyl S—CH₂-cycHex-CH₂—CH₂— methyl 5-fluoro 497 Me Pyridin-3-yl- CONH—(CH₂)₄— n-propyl 5-bromo 498 iProp 2-Aminothiazol-4yl- S—(CH₂)₄— n-propyl 5-chloro 6-bromo 499 Me 4-Methylthiazol-5-yl S—(CH₂)3— n-propyl 4-cyano 500 Me 2-Aminothiazol-4yl- S—(CH₂)₃— n-propyl 6-methoxy 501 Me 4-Methoxyphenyl COO—(CH₂)₃— n-propyl 4-cyano 502 Me N-Methyl-2-Pyrrolyl- S—(CH₂)₃— n-propyl 5-chloro 503 iProp 5-Methyl imida- S—(CH₂)₃— n-propyl 6-methansulfonyloxy zol-4-yl- 504 Me Cyclohexyl- S—(CH₂)₃— n-propyl 5-chloro 505 Me 3-Pyrrolyl S—(CH₂)₃— n-propyl 5-chloro 506 Ethyl 6-Chloro-biphenyl-2- S—(CH₂)₃— prop-2en-yl 5-bromo 507 Me 2-Thienyl S—(CH₂)₃— n-propyl H 508 Ethyl Pyridin-3-yl- S—(CH₂)₃— prop-2en-yl 5-bromo 509 cycProp 5-Methyl imida- S—(CH₂)₃— prop-2en-yl 6-methansulfonyloxy zol-4-yl- 510 Me Pyridin-3-yl- S—(CH₂)₃— methyl 4-cyano 511 Propyl 4-Methylthiazol-5-yl S—CH₂—CH═CH—CH₂— n-propyl 6-trifluoromethoxy 512 Ethyl Phenyl CO—(CH₂)₃— prop-2en-yl 5-chloro 513 Me 2,5-Di-methyl-fura- S—(CH₂)₃— n-propyl 6-methoxy H nyl-3- 514 Me 2-Thienyl S—CH₂—C(═CH₂)—CH₂ n-propyl 5-chloro 515 Me 5-Methyl imida- S—(CH₂)₃— prop-2en-yl 6-cyano /-methyl zol-4-yl- 516 Me Phenyl (CH₂)₄— n-propyl 5-methoxy 517 Me 4-Methoxyphenyl S—CH₂—C(═CH₂)—CH₂ n-propyl 4-cyano 518 Me Pyridin-4-yl- S—(CH₂)₃— n-propyl 5-methyl 519 Me 4-Jod-phenyl S—(CH₂)₃— n-propyl 6-methoxy 520 Me 3-Cyano-phenyl S—(CH₂)₃— n-propyl 5-methyl

If no meaning is given, R⁷ is hydrogen.

Examples of pharmaceutical administration forms

A) Tablets

Tablets of the following composition were pressed on a tabletting machine in the customary manner

40 mg of the substance from Example 1

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg of Aerosil® (chemically pure silicic acid in a submicroscopically fine dispersion)

6.75 mg of potato starch (as a 6% paste)

B) Sugar-coated Tablets

20 mg of the substance from Example 4

60 mg of core composition

70 mg of sugar-coating composition

The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone-vinyl acetate 60:40 copolymer. The sugar-coating composition consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets which have been prepared in this way are then provided with an enteric coating.

Biological investigations—receptor binding studies

1) D₃ Binding Test

Cloned human D₃-receptor-expressing CCL 1,3 mouse fibroblasts, obtainable from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.

Cell Preparation

The D₃-expressing cells were multiplied in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U of penicillin/ml and 0.2% streptomycin (GIBO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated for 5 min with 0.05% trypsin-containing PBS. After that, the mixture was neutralized with medium and the cells were collected by centrifuging at 300 g. In order to lyse the cells, the pellet was washed briefly with lysis buffer (5 mM Tris-HCl, pH 7.4, containing 10% glycerol) and after that incubated, at 4° C. for 30 min, at a concentration of 10⁷ cells/ml of lysis buffer. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.

Binding Tests

For the D₃-receptor binding test, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA), at a concentration of approx. 10⁶ cells/250 μl of test mixture, and incubated at 30° C. for 0.1 nM ¹²⁵iodosulpiride in the presence and absence of the test substance. The nonspecific binding was determined using 10⁻⁶ M spiperone.

After 60 min, the free radioligand and the bound radioligand were separated by filtering through GF/B glass fiber filters (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway), and the filters were washed with ice-cold Tris-HCl buffer, pH-7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by means of nonlinear regression analysis using the LIGAND program.

D₂ binding Test

Cell Culture

HEK-293 cells possessing stably expressed human dopamine D2A receptors were cultured in RPMI 1640 containing Glutamix I™ and 25 mM HEPES containing 10% fetal calf serum albumin. All the media contained 100 units of penicillin per mol and 100 μg/ml of streptomycin/ml. The cells were maintained at 37° C. in a moist atmosphere containing 5% CO₂.

The cells were prepared for the binding studies by trypsinizing them (0.05% solution of trypsin) at room temperature for 3-5 minutes. After that, the cells were centrifuged at 250 g for 10 minutes and treated with lysis buffer (5 mM Tris-HCl, 10% glycerol, pH 7.4) at 4° C. for 30 minutes. After centrifuging at 250 g for 10 minutes, the residue was stored at −20° C. until used.

Receptor Binding Tests

Low affinity state dopamine D₂ receptor using ¹²⁵I-spiperone (81 TBq/mmol, Du Pont de Nemours, Dreieich)

The test mixtures (1 ml) consisted of 1×10⁵ cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM MgCl₂ and 2 mM CaCl₂, pH 7.4 with HCl) and 0.1 mM ¹²⁵I-spiperone (total binding) or additionally 1 μM haloperidol (nonspecific binding) or test substance.

After the test mixtures had been incubated at 25° C. for 60 minutes, they were filtered through GM/B glass filters (Whatman, England) on a Skatron cell harvester (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The results were evaluated as described in a).

The K_(i) values were determined by way of nonlinear regression analysis using the LIGAND program or by converting the IC₅₀ values using the Cheng and Prusoff formula.

In these tests, the compounds according to the invention exhibit very good affinities for the D₃ receptor (<1μ molar, in particular <200 nmolar) and bond selectively to the D₃ receptor.

In table 3 the pK_(i)-D₃ values and selectivity (K_(i)(D₂)/K_(i)(D₃)) are given for the compounds of the examples 1, 14 and 26.

TABLE 3 Example pK_(i) (D₃)* Selectivity 1 9.05 71 14 7.82 46 26 8.06 157 *negative logarithm of K_(i) (D₃) [M] 

We claim:
 1. A triazole compound of the formula I

where R¹ is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₃-C₆-cycloalkyl or phenyl; R² is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR³, CONR³R⁴, NR³R⁴, SO₂R³, SO₂NR³R⁴ or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COR³, NR³R⁴, NO₂, SO₂R³, SO₂NR³R⁴ and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C₁-C₆-alkyl, C₁-C₆-alkoxy, NR³R⁴, CN, CF₃, CHF₂ or halogen; R³ and R⁴ are, independently of each other, H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, or phenyl; A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, CONR³, COO, CO, C₃-C₆-cycloalkyl and a double or triple bond; B is a radical of the following formula:

 where X is CH₂ or CH₂CH₂; R⁵ is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₃-C₆-cycloalkyl, C₂-C₆-alkenyl, which may be substituted by halogen, or C₂-C₆-alkynyl; R⁶, R⁷ and R⁸ are, independently of each other, selected from H, OH, C₁-C₆-alkoxy, SH, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, NO₂, SO₂R³, SO₂NR³R⁴, NHSO₂R³, NR³R⁴, and C₁-C₆-alkyl which is optionally substituted by OH, OC₁-C₆-alkyl, C₁-C₆-alkylthio, halogen or phenyl; or a salt thereof with a physiologically tolerated acid.
 2. A compound as claimed in claim 1 of the formula I, where X is CH₂CH₂.
 3. A compound as claimed in claim 1 of the formula I, where A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, a double bond or triple bond and C₃-C₆-cycloalkyl.
 4. A compound as claimed in claim 1 of the formula I, where R² is an aromatic radical which is unsubstituted or has one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, OH, C₁-C₆-alkoxy, phenyl, CN and halogen.
 5. A compound as claimed in claim 1 of the formula I, where R² is H, C₁-C₆-alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazoly or pyrazinyl.
 6. A compound as claimed in claim 1 of the formula I, where R¹ is H, C₁-C₆-alkyl or C₃-C₆-cycloalkyl.
 7. A compound as claimed in claim 1 of the formula I, where R⁶, R⁷ and R⁸ are selected, independently of each other, from H, C₁-C₆-alkyl, halogen-substituted C₁-C₆-alkyl, OH, C₁-C₆-alkoxy, C₁-C₆-akylthio-C₁-C₆-alkyl, halogen, CN, SO₂R³, SO₂NR³R⁴, CONR³R⁴ and NO₂.
 8. A compound as claimed in claim 1 of the formula I, where R¹ is H, C₁-C₆-alkyl or phenyl, R² is H, C₁-C₆-alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl, A is —SC₃-C₁₀-alkylene which may comprise a double bond or C₃-C₆-cycloalkyl, and R⁶, R⁷ and R⁸ are selected from H, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen and C₁-C₆-alkylthio-C₁-C₆-alkyl.
 9. A pharmaceutical which comprises at least one compound as claimed in claim 1, where appropriate together with physiologically acceptable excipients and/or adjuvants. 